Crystallization is typically viewed as a two step process: nucleation, or "birth" of new crystals, followed by crystal growth (Review--Myerson, A. S. 1993. Handbook of industrial crystallization. Butterworth-Heinemann. 43-52). Nucleation can be classified in two categories: primary and secondary. In primary nucleation, no seed crystals are present; whereas in secondary nucleation, presence of crystal surfaces has a catalyzing effect on the nucleation process.
Primary nucleation can be further subdivided as either homogeneous or heterogeneous. In homogeneous nucleation, the liquid is assumed to be free of any crystals or foreign particles, a situation rarely achieved. Due to fluctuations in local concentrations, ordered microregions appear. When these ordered clusters reach a critical size, nucleation occurs. In heterogeneous nucleation, foreign particles present in the bulk promote nucleation by reducing the energy required.
Despite years of research in the area of secondary nucleation, its mechanism and kinetics are still poorly understood. There are six proposed mechanisms: initial breeding, dendritic breeding, polycrystalline breeding, attrition breeding, contact nucleation, and fluid shear.
Initial breeding theory suggests that tiny crystallites that originate from the seed crystals behave as the nucleation sites. According to dendritic (needle) breeding theory, needle-like crystals form at high supersaturation levels. When they fragment, they serve as nucleation sites. At even higher supersaturation levels, formation and fragmentation of polycrystals provide the nucleation sites. Attrition breeding occurs at high stirring speeds, and involves macroabrasion of crystals; whereas contact nucleation involves microabrasion.
The theory of fluid shear nucleation suggests that a semi-ordered boundary layer present at an interface (crystal/bulk solution, crystal/melt, air/liquid, etc.) is scraped off into the bulk forming a semi-ordered cluster. As smaller clusters merge together and form larger ones, nucleation occurs when the critical size is achieved.
Crystallization by growth occurs when molecules adsorb to the surface of an existing crystal and order themselves to fit into the existing crystal structure, forming layers. As the layers accumulate, faces of the crystal begin to grow.
The compound 4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one of structural formula (I) ##STR2## is an inhibitor of 5.alpha.-reductase type 1, useful in treating acne vulgaris, sweat disorders, seborrhea, androgenic alopecia (also called "androgenetic alopecia"), and benign prostatic hyperplasia. The compound 4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one is disclosed in PCT publication WO 93/23419. Briefly, 4,7.beta.-dimethyl 4-aza-5.alpha.-cholestan-3-one oil is synthesized in a 9-step process starting with cholesteryl acetate. The final synthetic step in the process to manufacture 4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one results in an oil which does not respond to typical crystallization methods.
What is desired herein is a method for the crystallization of 4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one to produce the thermodynamically most stable crystalline polymorphic form of 4,7.beta.-dimethyl-4-aza-5.alpha.-cholestan-3-one.
Polymorphism can be defined as the ability of the same chemical substance to exist in different molecular packing arrangements. The different structures are referred to as polymorphs, polymorphic modifications, or forms. From a pharmaceutical standpoint, it is desirable to form a product in an energetically stable crystalline form. From a manufacturing process standpoint, it is desirable to achieve this crystalline form using techniques that are fast, reproducible and predictable. Furthermore, these techniques, which are defined by the present invention as operating parameters, should be predictive of success at different production scales, from lab to pilot plant to manufacturing scale.